The main objectives of this proposal are: 1) the biochemical and morphological study of glycoconjugate metabolism, including further characterization of the ectoglycosyltransferase system in normal and tumor cells, 2) the evaluation of membrane sugar-analogs and nucleotide-sugar-analogs for their capacity to interfere with glycoconjugate functions or metabolism, 3) the assessment of the potential of these analogs in tumor chemotherapy. The ectoglycosyltransferase system is composed of plasma membrane bound glycosyltransferases and their endogenous plasma membrane bound macro-molecular substrates which act as acceptors in the enzyme catalyzed addition of sugars. Using electron microscope autoradiography we have shown that these acceptors and enzymes are located on the L1210 leukemia cell surface and we now plan to characterize the substrate specificity of this ectoenzyme and the endogenous acceptors it glycosylates. These systems have been implicated in mechanisms related to cell to cell adhesion, recognition and communication, cell surface repair, and in binding circulating glycoconjugates. Differences in the biochemical composition and structure of the cell's surface glycocalyx and its ectoglycosyltransferase systems have been noted between tumor and normal cells. These membrane differences will be exploited in tumor chemotherapy by designing and utilizing agents which interfere with cellular glycoconjugate metabolism or interact with the ectoglycosyltransferase system. Membrane sugar analogs will be examined for cytotoxicity and specific effects on protein and glycoprotein biosynthesis. Metabolic studies will be carried out with some of the more active agents, including an assessment of drug effects on intracellular nucleotide and nucleotide-sugar pool sizes using high-pressure liquid chromatographic techniques. Drug toxicity reversal by natural sugars and nucleosides will be studied to understand the mechanism of action of these agents. It is expected that these investigations will result in the development of new agents which may specifically interfere with the metabolism or function of tumor cell plasma membrane glycoconjugate and thereby inhibit tumor growth and/or metastasis.